BRPI0718247A2 - COMPOUNDS 3-ISOBUTIL-9,10-DIMETOXY-1,3,4,6,7,11B-HEXAHYDRO-2H-PYRID [2,1-A] ISOQUINOLIN-2-OL SUBSTITUTED AND METHODS RELATED TO THEM - Google Patents

Description

“COMPOSIENTS 3-ISOBUTIL-9.10-DIMETOXY-1,3,4,6,7,11 B-HEXAHYDRO-2H-PYRENE [2,1-A] ISOQUINOLIN-2-OL REPLACED AND METHODS RELATED TO THEM”

FIELD OF INVENTION

This invention generally relates to 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-ol compounds substitutes, their preparation and methods for treating disorders by administering such compounds to a warm blooded animal in need thereof.

BACKGROUND OF THE INVENTION

3-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-one, also known as tetrabenazine (TBZ), has been used as a medicine for decades. Tetrabenazine is a potent, reversible inhibitor of catecholamine uptake by vesicular monoamine transporter-2 (VMAT2) (IC50 = 3.2 nM) (Scherman, et al., Proc.Natl. Acad. Sci. USA, (1983) ) 80: 584-8) and is currently used in the treatment of various hyperkinetic movement disorders. Side effects associated with TBZ include sedation, depression, akathisia and parkinsonism. Inhibition of VMAT2 by TBZ results in depletion of brain monoamines in vivo (Pettibone, D.J. et al., Eur. J. Pharma. (1984) 102: 431-6). TBZ also inhibits presynaptic and postsynaptic dopamine receptors in rat brain (Login, IS, et al., (1982) Ann. Neurology 12: 257-62; Rehes et al., J. Pharmacol. Exp Ther (1983) 225: 515-521). This off-target TBZ activity may be responsible for some of the observed side effects.

TBZ, which contains two chiral centers and is a racemic mixture of two stereoisomers, is rapidly and extensively metabolized in vivo to its reduced form, 3-isobutyl-9,10-dimethoxy-1,3,4,6,7, 11 b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-ol, also known as dihydrotetrabenazine (HTBZ). HTBZ is believed to exist as four individual isomers: (±) alpha-HTBZ and (±) beta-HTBZ. 2R, 3R, 11bR or (+) alpha-HTBZ are believed to be the absolute configuration of the active metabolite (Chirality 1997 9: 59-62). Despite its success in treating hyperkinetic disorders, tetrabenazine has low and variable bioavailability. Administration of tetrabenazine to humans is complicated by the first extensive passage metabolism and little or no tetrabenazine being observed in the urine.

There is a need in the art for tetrabenazine analogs to provide the advantageous properties of tetrabenazine without exposure of the body to all dihydrotetrabenazine stereoisomers. There is also a need for tetrabenazine analogs that exhibit a longer half life than tetrabenazine. There is also a need in the art for tetrabenazine analogs that exhibit greater selectivity for VMAT2 than tetrabenazine. The present invention provides a tetrabenazine analog which exposes the body to a dihydrotetrabenazine stereoisomer, exhibits greater selectivity for VMAT2 than tetrabazine, exhibits a longer half life than tetrabenazine and may exhibit lower variability in the required patient dose. patient.

BRIEF SUMMARY OF THE INVENTION In summary, this invention generally relates to 3-isobutyl-9,10-

substituted dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-ol, individual enantiomers thereof, as well as methods for their preparation and use and compositions - pharmaceutical compositions containing them. More specifically, the substituted 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-ol compounds of this invention have the following general structure (I):

(!)

including stereoisomers, pharmaceutically acceptable salts and solvates thereof, where R 1 is as defined below.

The 3-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-

The substituted isoquinolin-2-ol of this invention have utility in a wide range of therapeutic applications and can be used to treat various disorders including the family of hyperkinetic movement disorders. Additionally, these compounds may be useful in treating other disease states or conditions that are associated with inhibition of vesicular monoamine transporter 2 (VMAT2).

The methods of this invention include administering an effective amount of 3-20 isobutyl-9,10-dimethoxy-1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2 -ol substituted, preferably in the form of a pharmaceutical composition, to a mammal in need thereof. Thus, still in a further embodiment, pharmaceutical compositions containing one or more 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1- a] substituted isoquinolin-2-ol of this invention in combination with a pharmaceutically acceptable carrier and / or diluent.

These and other aspects of the invention will become clear with reference to the following detailed description. To this end, various references are set forth herein, which describe in more detail certain basic information, procedures, compounds and / or compositions and are incorporated herein by reference in their entirety. BRIEF DESCRIPTION OF THE FIGURES

Figures 1a, 1b, and 1c comprise three graphs showing the conversion of tetabenzazine, compound 2-1 and compound 3-1 to their respective metabolites in human hepatocytes.

Figures 2a - 2f comprise six graphs showing the stability profile of compounds 3-1 and 2-1 in rat, dog and human liver microsomes.

Figures 3a - 3d comprise four graphs showing the pharmacokinetic properties of compounds 2-1 and 3-1 in dogs and rats and 1 d. 1 in the mouse.

DETAILED DESCRIPTION OF THE INVENTION

As mentioned above, the present invention generally relates to 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] substituted isoquinolin-2-ol. The compounds of this invention have the following structure (I):

and pharmaceutically acceptable stereoisomers, salts and solvates thereof, where:

R1 is:

a) -C (= O) -0-alkyl; or

b) -C (= O) -C 1-6 alkanediyl,

wherein said C 1-6 alkanediyl is optionally substituted by a group selected from -NH-C (= NH) NH 2, -CO 2 H, -CO 2 Me 1 -SH, -C (O) NH 2, -NH 2, -SCH 3, phenyl, -OH, 4 -hydroxyphenyl, imidazolyl and indolyl.

As used herein, the above terms have the following meaning: "Alkyl" means a straight or branched, non-cyclic or cyclic, unsaturated or saturated aliphatic hydrocarbon containing from 1 to 10 carbon atoms, while the term "alkyl" C1-4 ”has the same meaning as alkyl, but contains from 1 to 4 carbon atoms. 'C1V alkyl' has the same meaning as alkyl but contains from 1 to 6 carbon atoms. Representative linear, saturated alkyl chains include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and the like; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, t-butyl, isopentyl, and the like. Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, and the like; while instilled cyclic alkyls include cyclopentenyl and cyclohexenyl, and the like. Cyclic alkyls include di and polyhomocyclic rings such as decalin and adamantyl. Unsaturated alkyls contain at least one double or triple bond between carbon atoms

OR

(I) as an "alkenyl" or "alkynyl", respectively). Representative straight or branched chain alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl,

1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and the like; while representative straight or branched chain alkynyls include acetylenyl-1-propynyl, 1-butynyl, 2-butynyl, 1-pentinyl, 2-pentinyl, 3-methyl-1-butynyl, and the like.

"C1V acanediyl" means a divalent C1-4 alkyl from which two hydrogen atoms have been taken from the same carbon atom or from different carbon atoms, such as, -CH2-, -CH2CH2 -, - CH (CH3) - - CH 2 CH 2 CH 2 -, -CH (CH 3) CH 2 CH 2 -, -CH 2 C (CH 3) 2 CH 2 -, and the like.

“Amino acid residue” means a structure and amino acid that does not have the

droxyl of the σ-carboxyl group. For example, the alanine residue is -C (= O) -CH (NH 2) CH 3.

In one embodiment, R 1 of structure (I) is -C (= 0) 0-alkyl as shown in structure (II) and in another embodiment, R 1 of structure (I) is -C (= 0) -C 1-6 alkanediyl -NH2 as shown in structure (III).

(II) (III)

In one embodiment, the C1-6 alkanediyl structure of structure (III) is (S) -1-amino-

2-methyl-propan-1-yl as shown in structure (IV). Structure (V) shows a fashion of structure (I) wherein R1 is -C (= O) C1-6 alkanediyl and C1-6 alkanediyl is substituted with -COOH.

In additional embodiments, R1 of structure (I) is an amino acid residue as shown in structure (VI). Structure (VII) shows one embodiment of structure (VI) wherein the amino acid residue is valine. amino acid residue Õ-vaüna

(SAW)

(VII)

In one embodiment, the compounds of the present invention may exist as the racemic mixture, as a diastereomeric pair or as the individual enantiomer or enantiomer mixture. Structure (VIII) shows ring numbering for 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2 compounds substituted ols of the invention. Stereocenters are located at positions 2, 3, and 11b of the ring system. The compounds of the present invention include the 2R, 3R, 11bR configuration as well as the

11bS, 2S1 3S1 11bR, and 2S, 3S, 11bS enantiomers. The 2R, 3R, 11bRe 2S, 3S, 11bS enantiomers are shown in structures (IX) and (X), respectively.

known methods, including the methods described in more detail in the Examples. In general, the compounds of structure (I) above may be manufactured by the following reaction schemes where all substituents are defined above unless otherwise indicated.

Reduction of a racemic mixture of R, R and S, S tetrabenazine with a boroid reducing agent provides dihydrotetrabenazine a. When the reducing agent is tri-sec-butyl lithium borohydride (L-Selectride), predominantly 2S, 3R, 11bRe and 2R, 3S, 11bS isomers will be generated. The use of sodium borohydride results in a mixture of all 20 4 stereoisomers. The remaining stereoisomers may be synthesized by taking any or all of the previously generated stereoisomers and reacting them with

2R, 3R, 11bS thiomers, 2R, 3S, 11bR, 2S, 3R, 11bR, 2R, 3S, 11bS, 2S, 3R,

OR

OR

OR

(I CAME)

(IX)

(X)

10

The compounds of the present invention may be prepared by synthetic techniques.

15

Reaction Scheme 1

OH

The dehydrating agent, such as phosphorus pentachloride to form the unsaturated compound which is then stereoselectively rehydrated, for example, a hydroboration procedure using borane-THF to form a borane complex which is oxidized to the appropriate dihydrotetrabenazine with hydrogen peroxide (Clarke et al., W02005077946). Racemic products may be further separated by chiral chromatography into individual enantiomers by chiral chromatography.

Reaction Scheme 2

The chloroformate intermediate c can be generated by treatment of α with phosgene or triphosgene. Treatment of c with an alcohol in the presence of a base such as DMAP generates carbonate product d. Alternatively, carbonate d may be generated directly by treating alcohol a with a pyrocarbonate under DMAP catalysis.

Reaction Scheme 3

Dihydrotetrabenazine a is condensed with a BOC protected amino acid employing 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and dimethylaminopyridine (DMAP) in dimethylformamide and methylene chloride, followed by deprotection of the funnel. BOC functionality, for example, with 50/50 trifluoroacetic acid / methylene chloride solution to provide e.g. Alternatively, dihydrotetrabenazine a may be condensed to a CBZ protected amino acid using DCC (1,3-dicycloexylcarbodiimide) followed by deprotection of CBZ functionality by hydrogenation under appropriate conditions.

The compounds of the present invention exhibit enhanced functionality for VMAT2 in

relation to tetrabenazine. As a result, they can provide desirable properties of tetrabenazine without all undesirable side effects. Furthermore, as shown in Figures 3a-3d, certain compounds of this invention, such as, for example, 2-1, unexpectedly provide a longer duration of action than tetrabenazine. This may be specifically beneficial because it may allow for an administration regimen that requires fewer doses per day than tetrabenazine. For example, while tetrabenazine is typically administered 2-3 times daily, certain compounds of this invention, such as, for example, compound 2-1, may be therapeutically effective when administered once daily. Thus, due to the unexpectedly longer duration of action provided by these compounds, a daily dose may be obtained.

The compounds of the present invention include the following esters:

(S) -2-Amino acid 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-yl ester -3-methyl butyric

The compounds of the present invention include the following carbonates:

3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a] isoquinyl-2-yl ester of carbonic acid ethyl ester

3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-yl ester of carbonic acid

3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-yl ester of carbonic acid pentyl ester

3-Isobutyl carbonic acid isobutyl ester 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-yl ester 3-Isobutyl ester -9,10-dimethoxy-1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-one

sec-butyl ester of carbonic acid

3-Methyl butyl ester 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-yl ester of carbonic acid ;

3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-yl ester of carbonic acid t-butyl ester;

The compounds of the present invention may generally be used as the free acid or free base. Alternatively, the compounds of this invention may be used in the form of acid or base addition salts. The acid addition salts of the free amino compounds of the present invention may be prepared by methods well known in the art, and may be formed of organic and inorganic acids. Appropriate organic acids include maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic, trifluoracetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, palearic, acid , glycolic, glutamic and benzenesulfonic acids. Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric acid 30 and nitric acids. Base addition salts include salts that form with the carboxylate anion and include salts formed with organic and inorganic cations, such as those selected from alkaline and alkaline earth metals (e.g. lithium, sodium, potassium, magnesium, barium and calcium), as well as the ammonium ion and substituted derivatives thereof (eg dibenzylammonium, benzylammonium, 2-hydroxyethylammonium and the like). Thus the term "pharmaceutically acceptable salt" of structure (I) is intended to encompass any and all acceptable salt forms.

With respect to stereoisomers, the compounds of structure (I) may have chiral centers and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. Additionally, some of the crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present invention. In addition, some of the compounds of structure (I) may also form solvates with water or other organic solvents. Such solvates are similarly included within the scope of this invention.

As mentioned above, the compounds of this invention and their salts may reduce the supply of monoamines in the central nervous system by inhibiting the human monoamine transporter 2 isoform (VMAT2). As such, these compounds and their salts may have utility over a wide range of therapeutic applications and may be used to treat a variety of disorders that are caused or linked to inhibition of the human monoamine transpotator 2 isoform. These disorders include disorder. - in hyperkinetics.

In one embodiment, the conditions that may be treated by the compounds of the

The present invention includes, but is not limited to the treatment of hyperkinetic disorders such as Huntington's disease, tardive dyskinesia, Tourette's syndrome, and tic disorder.

In another embodiment of the invention, the compounds of this invention and their salts may be hydrolyzed in the body of a mammal to compounds which may inhibit human monoamine 2 transporter isoform. As such, these compounds and salts thereof may be of additional utility in alteration of the in vivo properties of the metabolite in a mammal, such as the maximum concentration or duration of action.

In another embodiment of the invention, pharmaceutical compositions containing one or more monoamine resorption inhibitors are disclosed. For administration purposes, the compounds of the present invention may be formulated as pharmaceutical compositions. The pharmaceutical compositions of the present invention comprise a monoamine resorption inhibitor of the present invention and a pharmaceutically acceptable carrier and / or diluent. The VMAT2 inhibitor is present in the composition in an amount that is effective to treat a specific disorder, that is, in an amount sufficient to reduce the supply of monoamines in the central nervous system and preferably with patient-acceptable toxicity. Appropriate concentrations and dosages may be readily determined by one of skill in the art.

Pharmaceutically acceptable carriers and / or diluents are familiar to those skilled in the art. For compositions formulated as liquid solutions, acceptable carriers and / or diluents include brine and sterile water and may optionally include antioxidants, buffers, bacteriostats and other common additives. The compositions may also be formulated as pills, capsules, granules or tablets containing, in addition to the VMAT2 inhibitor, diluents, surface active and dispersing agents, binders and lubricants. One of skill in the art may additionally formulate the VMAT2 inhibitor in an appropriate manner and in accordance with accepted practice as disclosed in Remington's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton, PA 1990 .

In another embodiment, the present invention provides a method for treating central or peripheral nervous system disorders. Such methods include administering the compound of the present invention to a warm-blooded animal in an amount sufficient to treat the condition. In this context, "treating" includes prophylactic administration. Such methods include systemic administration of a VMAT2 inhibitor of this invention, preferably in the form of a pharmaceutical composition, as discussed above. As used herein, systemic administration includes oral and parenteral administration methods. For oral administration, suitable pharmaceutical compositions include powders, granules, pills, tablets and capsules as well as liquids, syrups, suspensions and emulsions. These compositions may also include flavorings, preservatives, suspending, thickening and emulsifying agents and other pharmaceutically acceptable additives. For parenteral administration, the compounds of the present invention may be prepared in aqueous injection solutions which may contain, in addition to the VMAT2 inhibitor, buffers, antioxidants, bacteriostats and other additives generally employed in such solutions.

EXAMPLES

HPLC methods for sample analysis

Retention Time, tR, in minutes

HPLC-MS Analytical Method 1

Platform: Agílent 1100 Series: Equipped with a self-sampler, a UV detector (220 nM and 254 nM), an EM detector (APCI);

HPLC column: Phenomenex Synergi-Max RP 80A, 2.0 x 50 mm column;

HPLC gradient: 1.0 mL / min, 10% acetonitrile in water to 90% acetonitrile in water in 2.5 minutes, maintaining 90% for 1 minute. Both acetonitrile and water have 0.25% TFA.

HPLC-MS Analytical Method 2

Platform: Agilent 1100 Series: Equipped with a self-sampler, a UV detector (220 nM and 254 nM), an EM detector (APCI);

HPLC column: Phenomenex Synergi-Max RP 80A, 2.0 x 50 mm column;

HPLC gradient: 1.0 mL / min, 5% acetonitrile in water to 95% acetonitrile in water in 13.5 minutes, maintaining 90% for 2 minutes. Both acetonitrile and water have 0.25% TFA.

HPLC-MS Analytical Method 3

Platform: Gilson 215 Autosampler, Dionex Thermostatted TCC-100 Column Enclosure maintained at 30 ° C, Dionex PDA-100 Photodiode Array Detector (220 nm and 254 nm), Dionex P680 HPLC Pump, Finnigan Single Square Thermal Mass Spectrometer MSQ (APCI)

HPLC column: Phenomenex Gemini 5μ C18 11OA1 4.6 x 150 mm HPLC gradient: 2.5 mL / min, 5% acetonitrile in water 90% acetonitrile in water 9 minutes and 86 seconds from acetonitrile a 90% in water 95% acetonitrile in water in 1 second, keeping at 95% for 1 minute and 19 seconds. Both acetonitrile and water have 0.04% NH 4 OH.

HPLC-MS Analytical Method 4

Platform: Gilson 215 Autosampler, Dionex Thermostatted TCC-100 Column Enclosure maintained at 30 ° C, Dionex PDA-100 Photodiode DetectorArray (220 nm and 254 nm), Dionex P680 HPLC Pump, Finnigan MSQ Single Square Thermal Mass Spectrometer (APCI)

HPLC column: Phenomenex Gemini 5μ C18 11OA, 3.0 x 150 mm HPLC gradient: 1.5 mL / min, 5% acetonitrile in water 90% acetonitrile in water 9 minutes and 86 seconds from acetonitrile 90% in water 95% acetonitrile in water in 1 second, keeping at 95% for 1 minute and 19 seconds. Both acetonitrile and water have 0.04% NH 4 OH.

Chiral Supercritical Fluid Chromatography for Chiral Separation Method 1 Platform: Autochem Berger Multigram Il SFC System Column: Chiralcel OD-H, 2.1 x 25 cm, SFC Column Modifier: 20% methanol

Circulation rate: 60 mL / min Pressure: 10 MPa Oven temperature: 35 ° C

Loading: about 14 mg / injection (methanol)

Chiral Supercritical Fluid Chromatography for Chiral Separation Method 2 Platform: Autochem Berger Multigram Il SFC System Column: Chiralpak AS-H, 2.1 x 25 cm, SFC Column Modifier: 20% methanol

Circulation rate: 60 mL / min Pressure: 10 MPa Oven temperature: 35 ° C Loading: 40 mg / injection (MeOH)

Chiral Supercritical Fluid Chromatography for Chiral Separation Method 3

Column: Chiralpak IA, 2.1 x 25 cm, SFC Column Modifier: 28% (Methanol / Acetone = 7: 3) Circulation Rate: 55 mL / min Pressure: 10 MPa Oven Temperature: 35 ° C Loading: 50 mg / injection The sample was dissolved in a 1: 1 mixture of Methanol / Acetone. The concentration

was 50 mg / mL.

EXAMPLE 1

(2R, 3R, 11 bR) -3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-ol ( (2R, 3R, 11bR) -dihydrotetrabenazine)

Step 1 A: 3-Dimethylaminomethyl-5-methylhexan-2-one

Dimethylamine HCl (90 g, 1.1 mol), 5-methyl-2-hexanone (450 mL, 3.3 mol) and paraformal aldehyde (50 g, 1.7 mol) were suspended in MeOH (80 mL) and Concentrated HCl (200 μί) was added. The reaction mixture was heated at 80 ° C for 12 hours. The mixture was allowed to cool to room temperature and 10% NaOH was added until basic. The entire mixture was extracted with Et 2 O (100 mL, 2 times). The organic layer was dried over MgSO4 and concentrated. The crude reaction mixture was columned through flash column chromatography (0.5: 9.5 MeOH: CH 2 Cl 2) to afford 30 g (175 mmol) of 3-dimethylaminomethyl-5-methylhexan-2-one. 1a in 16% yield.

Step 1B: 3-Dimethylaminomethyl-5-methylhexan-2-one methiodide To a round bottom flask was added 3-dimethylaminomethyl-5-methylhexan-2-one

1a (30 g, 175 mmol) and EtOAc (300 mL) followed by methyl iodide (22 mL, 351 mmol). The mixture was stirred overnight and a white precipitate formed. The precipitate was filtered, washed with Et 2 O (150 mL, 3 times) and dried to yield 3-dimethylaminomethyl-5-methylhexan-2-one 1b methiodide (44.9 g, 81% yield) as a white solid. in lanugem.

Step 1C: Tetrabenazine

To a round bottom flask was added 6,7-dimethoxy-3,4-dihydroisoquinoline (13 g, 67.8 mmol), 3-dimethylaminomethyl-5-methylhexan-2-one methide 1b (26 g, 81 4 mmol) and EtOH (130 mL). The suspension was heated to 80 ° C overnight. The reaction mixture was allowed to cool to room temperature and H 2 O (200 mL) was added forming a precipitate. EtOH was removed in vacuo and CH 2 Cl 2 (400 mL) was added. A 10% NaOH solution was added to the mixture until it became basic. The aqueous layer was then extracted 3 times with CH 2 Cl 2 (250 mL). The organic layers were combined, dried over MgSO4 and concentrated. The crude reaction mixture was purified via flash column chromatography (0.5: 9.5 acetone: CH 2 Cl 2) and further recrystallized from EtOAc and Hexanes to provide 16.1 g (51 mmol) of a racemic mixture of ( 3S, 11bS) and (3R, 11bR) -3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-pyrido [2,1- a] isoquinolin-2-one 1c (tetrabenazine, TBZ) in 75% yield. The tetrabenazine enantiomers were separated by SFC employing a Chiralpak AD-H column with 15% CAN / MeOH plus 0.5% DMEA at 2.5 mL / min at 10 MPa and 35 ° C to yield 4.3 g of (3R, 11bR) -tetrabenazine 1 c. 1 and 4.3 g of (3S, 11bS) -tetrabenazine 1c.2.

(3R, 11bR) -tetrabenazine 1c.1: Calculated MS: (317); Found 318.7 (Μ + H).

(3S, 11bS) -tetrabenazine 1c.2: MS calculated: (317); Found 318.7 (Μ + H).

Step 1 D: (2R.3R.11 bRV3-lsobutyl-9.10-dimethoxy-1.3.4.6.7.11 b-hexahydro-2H-pyridor2.1-alisoauinolin-2-ol

(3R, 11bR) -Tetrabenazine 1 c. 1 (2 g, 6.3 mmol) was dissolved in EtOH (70 mL) and cooled to 0 ° C. Sodium borohydride (261 mg, 6.9 mmol) was then added portionwise at 0 ° C. The reaction was complete after 30 minutes and was saturated with saturated NH 4 Cl (4 mL). The white precipitate formed was filtered off and washed with EtOH (5 mL, 2 times). EtOH was removed in vacuo and the aqueous layer extracted 3 times with CH 2 Cl 2 (50 mL). The organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by flash column chromatography (0.5: 9.5 MeOH: CH 2 Cl 2) to provide 1.6 g (5 mmol) of (2R, 3R, 11bR) -3-isobutyl-9,10 -dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-ol ((2R, 3R, 11bR) -dihydrotetrabenazine) 1 d. 1 and 410 mg (1.3 mmol) of (2S, 3R, 11bR) -3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2.1 -a] isoquinolin-2-ol ((2S, 3R, 11bR) -dihydrotetrabenazine) 1 d.2.

(2R, 3R, 11bR) -Dihydrotetrabenazine 1 d. 1: MS calculated: (319); Found 320.3 (M

+ H).

(2S, 3R, 11bR) -Dihydrotetrabenazine 1d.2: MS calculated: (319); Found 320.3 (M

+ H).

EXAMPLE 2

(2R.3R, 11bR) -3-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido ester [2,1-

(S) -2-Amino-3-methyl-butyric acid isoquinolin-2-yl

Step 2A: (S) - Acid (2R.3R. 11 bR) -3-Isobutyl-9.10-dimethoxy-1.3.4.6.7.11b-hexahydro-2H-pyrido-2,1-a1isoauinolin-2-yl ester 2-amino-3-methylbutyric

(2R, 3R, 11bR) -3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-30a] isoquinolin-2-ol 1 d. 1 (200 mg, 0.63 mmol) was dissolved in 3 mL of anhydrous CH 2 Cl 2 and DMAP (75.0 mg, 0.63 mmol) and Cbz-L-valine (190 mg, 0.75 mmol) were added and mixture stirred for 5 minutes. DCC (155 mg, 0.75 mmol) was added and a white precipitate formed immediately. The mixture was stirred overnight then filtered and concentrated. Purification by flash column chromatography (0.2: 9.8, MeOH: CH 2 Cl 2) provided 35 360 mg (0.63 mmol) of (2R, 3R, 11bR) -3-isobutyl-9,10-dimethoxy ester. 2-Benzyloxycarbonylamino-3-methylbutyric acid 1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-yl 2a as a pale yellow solid in quantitative yield. Compound 2a (163 mg, 0.29 mmol) was dissolved in MeOH (10 mL) and Pd / C was added and the mixture was purged with H 2. The mixture was stirred overnight, filtered through celite and concentrated. Purification via flash column chromatography (0.5: 9.5, MeOH: CH 2 Cl 2) provided 105 mg (0.25 mmol) of the ester (2R, 3R, 11bR) -3-isobutyl-9,10- (S) -2-Amino-3-methyl-2-dimethoxy-1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-5 a] isoquinolin-2-yl butyric acid in 85% yield. MS calculated: (419); Found 419.3 (Μ + H)

Additional compounds synthesized by the same procedure employing different amino acids include:

(2R, 3R, 11bR) -3-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-yl ester 2-2 of (R) -2-amino-4-methylpentanoic acid. MS calculated: (433); Found 433.4 (+ H);

(2R, 3R, 11bR) -3-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-yl ester 2-3 of (S) -2-amino-4-methylpentanoic acid. MS calculated: (433); Found 433.4 (+ H);

1 - ((2R, 3R, 11bR) -3-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-ester 4-methyl ester

(S) -2-Amino-succinic acid hexahydro-2H-pyrido [2,1-a] isoquinolin-2-yl) 2-4. MS calculated: (449); Found 449.3 (M + H);

(2R, 3R, 11bR) -3-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-yl ester 2-5 of 2-amino-2-methylpropionic acid. MS calculated: (405); Found 405.3 (M + H);

(2R, 3R, 11bR) -3-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-yl ester 2-6 of (R) -2-amino-propionic acid. MS calculated: (391); Found

391.3 (M + H);

(2R, 3R, 11bR) -3-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-yl ester 2-7 of (S) -2-amino-propionic acid. MS calculated: (391); Found

391.3 (+ H).

(2R, 3R, 11bR) -3-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-yl ester 2-8 of (R) -2-amino-3-methylbutyric acid. MS calculated: (419); Found 419.4 (Μ + H)

(2R, 3R, 11bR) -3-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido ester [2,1-

a] isoquinolin-2-yl 2-9 of aminoacetic acid. MS calculated: (377); Found 377.3 (M + H)

EXAMPLE 3

(2R, 3R, 11bR) -3-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-ester ethyl ester carbonic acid ila

Step 3A: Ether Ethyl Ester (2R.3R.11bRK3-isobutyl-9.10-dimethoxy-1.3.4.6.7.11b-

carbonic acid hexahydro-2H-pyrido-2,1-a1isoauinolin-2-yl 3-1 (2R, 3R, 11 bR) -3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11 b -hydro-2H-pyrido [2,1-

a] isoquinolin-2-ol 1 d. 1 (100 mg, 0.31 mmol) was dissolved in 3 mL of anhydrous CH 2 Cl 2 and DMAP (1.0 mg, 0.01 mmol) and pyridine (51 pL, 0.63 mmol) were added followed by dropwise addition. - droplet of ethyl chloroformate (45 µL, 0.47 mmol). The reaction was allowed to stir 5 overnight and diluted with CH 2 Cl 2 (10 mL) and extracted from saturated NH 4 Cl (5 mL). The organic layer was dried over MgSO4 and concentrated. The crude product was purified by flash column chromatography (1: 9, acetone: CH 2 Cl 2) to afford 88 mg (2.25 mmol) of

3-1 as a pale yellow foam in 72% yield. MS calculated: (392); Found 392.3 (Μ + H).

They were also prepared by the above procedure:

(2R, 3R, 11bR) -3-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-ester methyl ester 3-2a of carbonic acid in 37% yield. MS calculated: (378); Found 378.1 (Μ + H)

(2R, 3R, 11bR) -3-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-ester butyl ester 3-3a of carbonic acid in 46% yield. MS calculated: (420); Found 420.1 (Μ + H)

EXAMPLE 4

Method for Determining Compound Stability in Human Hepatocytes Cryopreserved human hepatocytes from 12 donor individuals were deconverted according to the manufacturer's instructions and grouped. Cell viability was determined to be greater than 85%. TBZ (1 μΜ) was incubated with individual human hepatocytes (1x106 cells / mL) at 37 ° C with 95% O2 and 5% CO2 for 9, 5, 15, 30 and 60 minutes. TBZ in DMSO was added to obtain 1.0 μΜ (DMSO was then less than 0.5% volume / volume). All concentrations and cell content were in relation to the final incubation volume of 100 μί. Incubation was terminated by mixing 100 μί of ice-cold acetonitrile in 1% formic acid containing dextromethorphan (1.0 μΜ) as internal standard for LC / MS analysis. Precipitated proteins were removed by centrifugation (1,500-2,500 x g for 30 minutes at 15 ° C).

Briefly, samples were separated with a gradient 30 HPLC method by Acquity UPLC systems consisting of a pump, a column heater (40 ° C) and a vacuum / mobile phase degasser tray. Mobile phase A was water in 0.1% formic acid and mobile phase B was acetonitrile in 0.1% formic acid. The gradient elution was as follows: mobile phase B: 0-10% in 0-0.75 minutes, 40-90% in 1.25-1.5 minutes, 90-0% in 1, 75-2.0 minutes and the operating time was 3 minutes. The reverse phase 35 column was a BEH C18 column (50x2.1 mm, 1.7 μΓη). The circulation rate was 0.8 mL / min and the injection volume was 7.5 pL. Samples were monitored with API-3000 mass spectrometer and positive mode ESI ion source, TBZ m / z 318.4> 220.4, HTBZ m / z 320.3> 302.3 and dextromethorphan m / z 272.2> 147.2.

Figures 1a, 1b, and 1c show the conversion of tetrabenazine, compound 2-1 and compound 3-1 in human hepatocytes to HTBZ for tetrabenazine and to 1 d. 1 for compounds 2-1 and 3-1. Tetrabenazine and compound 3-1 showed this conversion to be rapid while that of compound 2-1 was comparatively slow.

EXAMPLE 5

Method for Determining Compound Stability in Mammalian Liver Microsomes

In summary, pooled human liver microsomes (0.1 or 0.5 mg / mL; n> 10; mixed gender) were incubated at 37 ° C with the test compound in the presence of a NADPH generation system. containing 50 mM, pH 7.4 potassium phosphate buffer, 3 mM magnesium chloride, 1 mM EDTA, 1 mM NADP, 5 mM G-6-P, and 1 unit / ml G- 6-PD.

Incubations were conducted in six 2.0-mL modified 15-well 96-well plates in 1 μΜ of each compound (0.01% DMSO) with a total volume of 250 μΙ. Each plate, representing a single time point, contained 96 Titertube® Microtubes allowing duplicates of the 48 compounds at each time point (0, 5, 10, 20, 40 and 60 minutes). The reaction was stopped by the addition of an appropriate stop reagent (0.3 mL acetonitrile containing a proprietary internal standard). Precipitated proteins were removed by centrifugation for 15 minutes at 3,000 rpm and the supernatant fluid (~ 0.0 mL) was analyzed by LC / MS for the percentage of remaining parent compound.

Samples were separated with a gradient HPLC method by Acquity LC systems consisting of a pump, a column heater (40 ° C), and a vacuum / mobile phase degasser tray. Mobile phase A was water in 0.1% formic acid and mobile phase B was acetonitrile in 0.1% formic acid. Gradient elution was as follows: mobile phase B: 0-30% at 0-0.30 minutes, 30-98% at 0.7-1.1 minutes, 98% at 1.50-1.51 minutes , and the operating time was 3 minutes to 3-1; Mobile phase B: 5-98% at 0.5-2.5 minutes, 98-5% at 4.0-4.1 minutes and the operating time was 6 1/2 minutes to 2-1. The reverse phase column was a Luna C18 column (20x2 mm, 5 μΐη) for 3-1 and a 30 Synergi C18 column (150x2 mm, 5 μίτι) for 2-1. The circulation rate was 0.55 mL / min for 3-1 and 0.4 mL / min for 2-1 and the injection volume was 20 μί. Samples were monitored with API-3000 mass spectrometer and positive mode ESI ion source, TBZ m / z

318.4> 220.4, HTBZ m / z 320.3> 302.3 and dextromethorphan m / z 272.2> 147.2.

Figures 2a to 2f show the conversion of compound 2-1 and compound 3-1 into rat, dog and human liver microsomes in 1d.1. In each species, the conversion of compound 2-1 into 1 d. 1 was slower than the conversion seen in the case of compound 3-1 to compound 1 d. 1. EXAMPLE 6

Pharmacokinetic Evaluation (PK)

Animal Method:

1. Mouse

In summary, a single oral dose (10 mg / kg) of 2-1 and 3-1 in 10% PEG in

0.25% tilcellulose in milli Q water was administered to rats (3 rats / dose) for pharmacokinetic evaluation. Serial sampling was used to collect blood samples, which were taken from each treated animal at nine time points, ranging from pre-dose to 24 hours post-dose (0, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours) for oral administration. Blood samples were stored at -80 ° C or below until analysis.

2. Dog

In summary, a single oral dose (6.1 mg / kg for 3-1 and 10 mg / kg for 2-1) in 10% PEG in methylcellulose in milli Q water was administered to dogs (3 dogs / dose) for a pharmacokinetic evaluation. Serial sampling was used to collect 15 blood samples that were taken from each treated animal at nine time points ranging from pre-dose to 24 hours post-dose (0, 0.25, 0.5, 1, 1.5 , 2, 4, 6, 8, 12, 24, 36 and 48 hours) for oral administration. Plasma samples were stored at -80 ° C or below until analysis.

General Bioanalytical Method:

Blood samples were thawed on ice and 50 μί of plasma were

transferred to a 96-well plate. Plasma proteins were precipitated by the addition of 150 µl of pre-cooled acetonitrile (ACN) containing 75 ng / mL internal standard. An additional 50 µl ACN / water (60:40) was added to each sample. Calibration curve samples were prepared by serial dilution in ACN / water (60:40). Fifty µL of each standard sample was transferred to a 96-well plate followed by the addition of 150 µL of acetonitrile (ACN) containing 75 ng / mL internal standard and 50 µL of inactive rat plasma. The plates were capped, mixed and centrifuged at 3,000 rpm for 20 minutes. The supernatant was collected and injected into an LC-MS / MS system for quantitation. The non-validated test method showed good linearity, specificity and accuracy for 3-1, 2-1 and 1 d. 1 in a concentration range of 1 to 1,000 ng / mL and the low limit of quantitation of 3-1, 2-1 and 1d.1 were all at 1 ng / mL. Three sets of QC samples (4, 40, 400, 800 ng / ml) for 3-1, 2-1 and 1d.1 were used as quality control for the necessary studies and prepared in the same way as the standard. . Quantification was performed by adjusting the maximum area ratios for a heavy linear calibration curve (1 / x2).

Pharmacokinetic Method:

Descriptive pharmacokinetics were derived and evaluated based on plasma concentrations of 3-1, 2-1 and 1 d. 1 of each mouse. Pharmacokinetic parameters were determined using Non Behavioral Analysis of plasma concentration-time profile of 3-1, 2-1 and 1 d. 1 in the WinNon-Iin Professional Version 5.0.1 pharmacokinetic modeling software program (Pharsight Corporation, Mountain View, CA).

Figure 3a shows that the rat plasma concentration time profile of the rat

compound 1 d. 1 from 3-1 and 1 d. 1 administered orally is not distinguishable. None 3-

1 was detected in rat plasma after oral administration of 3-1.

Figure 3b shows the rat plasma concentration time profile of compound 1 d. 1 and 2-1 after oral administration of 2-1.

Figure 3c shows the time profile of the dog's plasma concentration of the compound.

to 1 d. 1 and 3-1 after oral administration of 3-1.

Figure 3d shows the time profile of the dog's plasma concentration of compound 1 d. 1 and 2-1 after oral administration of 2-1.

These figures show that the plasma half life of 1 d. 1 when oral administration of compound 2-1 is 2-3 times greater than oral administration of compound 3-

1.

EXAMPLE 7

Vesicular Monoamine Isoform 2 Binding Assay (VMAT2) (adapted from Teng, et al., J. Neurochem. 71, 258-65, 1998)

Procedure A:

Preparation of rat stretch mark vesicles

Stretch marks from three rats are grouped and homogenized in 0.32 M sucrose. The homogenate is then centrifuged at 2000xg for 10 minutes at 4 ° C and the resulting supernatant is centrifuged at 10.000xg for 30 minutes at 4 ° C. The resulting microsphere containing the enriched synaptosomal fraction (2 mL) is subjected to osmotic shock by the addition of 7 mL of distilled H2O and subsequently the suspension is homogenized. Osmolarity is restored by adding 0.9 mL of 0.25 M HEPES and 0.9 mL of neutral L (+) - tartaric acid dipotassium salt buffer (pH 7.5), followed by 20 minutes of centrifugation (20,000xg at 4 ° C). The supernatant is then centrifuged for 60 minutes (55,000xg at 4 ° C) and the resulting supernatant is centrifuged for 45 minutes (100,000xg at 4 ° C). The resulting microsphere is resuspended in 25 mM HEPES, 100 mM L - (+) - tartaric acid dipotassium salt, 5 mM MgCl2, 10 mM NaCl, 0.05 mM EGTA, pH 7.5 to a 1-2 mg / mL and stored at -80 ° C for up to 3 weeks without appreciable loss of binding activity. Immediately prior to use, the final microsphere is resuspended in the binding buffer (25 mM HEPES, 100 mM L - (+) - tartaric acid dipotassium salt, 5 mM MgCl 2, 10 mM NaCl, 0.05 mM EGTA, 0.1 mM EDTA, 1.7 mM ascorbic acid, pH 7.4). [3H] -dihydrotetrabenazine (DHTBZ) binding

Aliquots of the gallbladder suspension (0.16 mL, 15 μg protein / mL) are incubated with competing compounds (ranging from 1E-6M to 1E-12M) and 2 nM of [3H] dihydrotetrabenazine (HTBZ; specific activity). : 20 Ci / mmol, American Radiolabeled Chemicals, Inc) for 1 hour at room temperature in a total volume of 0.5 mL. The reaction is terminated by rapid filtration of samples on Whatman GF / F filters using a Brandel cell harvester. Non-specific binding is determined using 20 μΜ of tetrabenazine (TBZ). The filters are previously soaked for 2 hours with ice cold polyethyleneimine (0.5%). After the filters are washed three times with ice-cold buffer, 10 they are placed in scintillation vials with 10 mL scintillation cocktail. Binding radioactivity is determined by scintillation spectroscopy.

Procedure B:

The procedure was adapted from that described previously (Near, (1986), Mol. Pharmacol. 30: 252-7). Sprague-Dawley rat forebrain homogenates were prepared by homogenization and centrifugal washing as described previously (Hoare et al., (2003) Peptides 24: 1881-97). In a total volume of 0.2 mL in low-binding 96-well plates (Corning # 3605), twelve concentrations of HTBZ isomer or analog competed against 6 nM 3H-dihydrotetrabenezin (American Radiolabeied Chemicals, Kd 2.6 nM) in the homogenate. of rat forebrain (100 μg membrane protein per well) in a VMAT2 binding buffer (Dulbecco phosphate buffered brine, 1mM EDTA, pH 7.4). Following incubation at 25 ° C for two hours, the binding radioligant was collected by rapid filtration over GF / B fiberglass filters using a Unifilter-96 Harvester (PerkinEImer). Filter plates were pretreated for 10 minutes with 0.1% polyethylenimine and then washed with 800 μΙ of VMAT2 Binding Buffer. Binding radioligand was quantified by scintillation counting using an NXT Bench Counter (PerkinEImer).

Table 1. VMAT2 affinity from competitive binding studies PKi Compound (n) Ki (nM) 2R, 3R, HbR-HTBZ 8.7 ± 0.2 (6) 1.9 2S, 3R, HbR-HTBZ 7 9 ± 0.1 (5) 13 2S, 3S, 11bS-HTBZ 6.7 ± 0.1 (3) 202 2R, 3S, 11bS-HTBZ 6.1 ± 0.1 (4) 714 Compound 3-1 7.9 ± 0.1 (2) 14 Compound 2-1 6.7 ± 0.2 (2) 187 Data are an average ± SD for at least two independent experiments. Ki values were determined using a 1.2 nM Kd value for rat striated membranes (Roland et al. 2000). EXAMPLE 8

Receptor Selectivity Binding Assays

The four HTBZ stereoisomers and compounds of the present invention were tested for receptor specificity against a panel of 80 receptors, carrier 5 ion channels (High Performance Profile, Cerep, S.A.). Subsequently, the compounds were tested in the competition binding assays selected at a wide range of concentrations to determine their affinity for the receptors described below.

(a) Dopamine D2S Receptor:

Reference: Grandy et al. (1989) Proc. Natl. Acad. Know. USA 86: 9762-6

Source: Recombinant Human (CHO cells)

Binder: [3H] spiperone, 1.0 nM

Incubation time / temperature: 90 min / 25 ° C

Incubation Buffer: 50 mM HEPES, 100 mM NaCl, 1 mM EDTA, 3 mM MgCl 2, pH 7.4

Non-specific binder: clozapine (10 μΜ)

Kd: 27 pM Bmax: 6.9 pmol / mg Specific Binding: 600 cpm Quantitation Method: Scintillation Count

(b) Dopamine D4.4 Receptor:

Reference: Van Tol et al. (1992) Nature, 358: 149-152.

Source: Recombinant Human (CHO cells)

Binder: [3H] spiperone, 0.3 nM Incubation time / temperature: 60 min./22°C

Non-specific binder: (+) butaclamol (10 μΜ)

Kd: 0.19 nM

Quantification Method: Scintillation Count

Table 2. Receptor selectivity binding data 2 R, 3 R, 2 S, 3 R1 2 S, 3S, 2 R, 3 S, 3-1 2-1 HbR-HTBZ HbR-HbS-HbS-HTBZ HTBZ HTBZ D2S (h) -6% 17% 192 57 15% 2% inhibition inhibition inhibition inhibition 10 μιτι 30 μΜ to 10 μΜ to 10 μΜ D4.4 0% 30% from 9% of 67 15% 13% of (h) inhibition at 1 inhibition inhibition at 1 inhibition inhibition μΜ 10 μΜ μΜ at 10 μ at 10 μΜ = M The values shown are both Ki (nM) and% inhibition at the concentration tested. 2R, 3R, 11 bft-HTBZ and those of the 2R, 3R, 11 bft-HTBZ structural analogs, compounds 2-1 and 3-1, demonstrated selectivity for VMAT2. In contrast, 2S, 3S, 11bS and 2R, 3S, 11bS HTBZ stereoisomers exhibited high binding affinity for D2 (S). The 2S, 3R, 11bR HTBZ showed some minor inhibition at the tested dopamine receptors. This off-target activity of certain HTBZ isomers may contribute to some of the side effects observed with TBZ.

EXAMPLE 9

VMAT2 inhibitor-induced reductions in Iocomotor activity Mice (Sprague-Dawley, 100-300 g) are adapted to individual housing for at least 3 days prior to testing. Rats receive oral, intraperitoneal, subcutaneous or intravenous test substances (1-100 mg / kg) or vehicle controls. Following a pretreatment time of 15-60 minutes, the rats are placed in a clean cage surrounded by photocell detectors (San Diego Instruments). Mouse Iocomotive activity is detected by breaks in the photocell beams and activity is defined as the number of beam breaks per section. Observation periods ranged from 15 minutes to 2 hours. New compound effects are compared to vehicle and positive control effects (diazepam at 3 mg / kg) as one-way ANOVA, followed by Neuman-Keul and Student post hoc analysis. Eight to ten rats were used for test condition. EXAMPLE 10 VMAT2 Inhibitor Induced Ptosis

Mice (Sprague-Dawley, 100-300 g) are housed in individual housing for at least 3 days prior to testing. Rats receive oral, intraperitoneal, subcutaneous or intravenous test substances (1-100 mg / kg) or vehicle controls. Following a pretreatment time of 15 minutes, the rats are placed in a clean cage for observation of ptosis. Ptosis is evaluated on a four-point scale: eyes wide open = 0, eyes% closed = 1, eyes 1/4 closed = 2, eyes% closed = 3 and eyes fully closed = 4. Measurements were taken at 15 minutes to 3 hours after administration of the compounds. New effects of the compound are compared with vehicle effects with one-way ANOVA, followed by post hoc 30 analysis by Neuman-Keul and Student. Eight to ten rats were used for test condition.

It will be appreciated that while specific embodiments of the invention have been described herein for illustration purposes, various modifications may be made without departing from the spirit and scope of the invention. Accordingly, the invention is not limited except by the appended claims.

Claims (8)

1. A compound, characterized in that it has the following structure: <formula> formula see original document page 22 </formula> or a pharmaceutically acceptable stereoisomer, salt or solvate thereof, where: Ri is a) - C (= O) -O-alkyl; or b) -C (= O) -C1 alkanediyl -NH2, wherein said C1-6 alkanediyl is optionally substituted by a group selected from -NH-C (= NH) NH2, -CO2H1 -CO2Me1 -SH1 -C (O ) NH 2, -NH 2, -SCH 3 phenyl, -OH, 4-hydroxyphenyl, imidazolyl and indolyl. A compound according to claim 1, characterized in that the compound is 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido ester [2.1 a] 2-amino-3-methylbutyric acid isoquinolin-2-yl or a pharmaceutically acceptable stereoisomer, salt or solvate thereof. A compound according to claim 2, characterized in that the compound is (2R, 3R, 11bR) -3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydroester. 2-Amino-3-methylbutyric acid pyrido [2,1-a] isoquinolin-2-yl or a pharmaceutically acceptable stereoisomer, salt or solvate thereof. A compound according to claim 3, characterized in that the compound is (2R, 3R, 11bR) -3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydroester. (S) -2-Amino-3-methyl-butyric acid -2H-pyrido [2,1-a] isoquinolin-2-yl or a pharmaceutically acceptable stereoisomer, salt or solvate thereof. Pharmaceutical composition, characterized in that it comprises a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent. Pharmaceutical composition according to claim 5, characterized in that the compound is (2R, 3R, 11bR) -3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- (S) -2-Amino-3-methyl-butyric acid hexahydro-2H-pyrido [2,1-a] isoquinolin-2-yl or a pharmaceutically acceptable stereoisomer, salt or solvate thereof. A method for treating a hyperkinetic disorder, which comprises administering to an individual in need thereof a pharmaceutically effective amount of a pharmaceutical composition according to claim 5. A method according to claim 7, characterized in that the hyperkinetic disorder is Huntington's disease, tardive dyskinesia, Tourette's syndrome or tics.